https://rapm.bmj.com/content/rapm/early/2021/10/01/rapm-2021-103031.full.pdf

Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group.

With an aging population, there is a proportional increase in the prevalence of intervertebral disc diseases. Intervertebral disc diseases are the leading cause of lower back pain and disability. With a high prevalence of asymptomatic intervertebral disc diseases, there is a need for accurate diagnosis, which is key to management. A thorough understanding of the pathophysiology and clinical manifestation aids in understanding the natural history of these conditions. Recent developments in radiological and biomarker investigations have potential to provide noninvasive alternatives to the gold standard, invasive discogram. There is a large volume of literature on the management of intervertebral disc diseases, which we categorized into five headings: (a) Relief of pain by conservative management, (b) restorative treatment by molecular therapy, (c) reconstructive treatment by percutaneous intervertebral disc techniques, (d) relieving compression and replacement surgery, and (e) rigid fusion surgery. This review article aims to provide an overview on various current diagnostic and treatment options and discuss the interplay between each arms of these scientific and treatment advancements, hence providing an outlook of their potential future developments and collaborations in the management of intervertebral disc diseases.

Intervertebral Disc Diseases PART 2: A Review of the Current Diagnostic and Treatment Strategies for Intervertebral Disc Disease

Low back pain (LBP) in one of the most disabling symptoms affecting nearly 80% of the population worldwide. Its primary cause seems to be intervertebral disc degeneration (IDD): a chronic and progressive process characterized by loss of viable cells and extracellular matrix (ECM) breakdown within the intervertebral disc (IVD) especially in its inner region, the nucleus pulposus (NP). Over the last decades, innovative biological treatments have been investigated in order to restore the original healthy IVD environment and achieve disc regeneration. Mesenchymal stem cells (MSCs) have been widely exploited in regenerative medicine for their capacity to be easily harvested and be able to differentiate along the osteogenic, chondrogenic, and adipogenic lineages and to secrete a wide range of trophic factors that promote tissue homeostasis along with immunomodulation and anti-inflammation. Several in vitro and preclinical studies have demonstrated that MSCs are able to acquire a NP cell-like phenotype and to synthesize structural components of the ECM as well as trophic and anti-inflammatory mediators that may support resident cell activity. However, due to its unique anatomical location and function, the IVD presents distinctive features: avascularity, hypoxia, low glucose concentration, low pH, hyperosmolarity, and mechanical loading. Such conditions establish a hostile microenvironment for both resident and exogenously administered cells, which limited the efficacy of intradiscal cell therapy in diverse investigations. This review is aimed at describing the characteristics of the healthy and degenerated IVD microenvironment and how such features influence both resident cells and MSC viability and biological activity. Furthermore, we focused on how recent research has tried to overcome the obstacles coming from the IVD microenvironment by developing innovative cell therapies and functionalized bioscaffolds.

/pdf/interaction-between-mesenchymal-stem-cells-and-4ef6e4m4am.pdf

Interaction between Mesenchymal Stem Cells and Intervertebral Disc Microenvironment: From Cell Therapy to Tissue Engineering.

Intervertebral disc (IVD) herniation and degeneration contributes significantly to low back pain (LBP), of which the molecular pathogenesis is not fully understood. Disc herniation may cause LBP and radicular pain, but not all LBP patients have disc herniation. Degenerated discs could be the source of pain, but not all degenerated discs are symptomatic. We previously found that disc degeneration and herniation accompanied by inflammation. We further found that anti‐inflammatory molecules blocked immune responses, alleviated IVD degeneration and pain. Based on our recent findings and the work of others, we hypothesize that immune system may play a prominent role in the production of disc herniation or disc degeneration associated pain. While the nucleus pulposus (NP) is an immune‐privileged organ, the damage of the physical barrier between NP and systemic circulation, or the innervation and vascularization of the degenerated NP, on one hand exposes NP as a foreign antigen to immune system, and on the other hand presents compression on the nerve root or dorsal root ganglion (DRG), which both elicit immune responses induced by immune cells and their mediators. The inflammation can remain for a long time at remote distance, with various types of cytokines and immune cells involved in this pain‐inducing process. In this review, we aim to revisit the autoimmunity of the NP, immune cell infiltration after break of physical barrier, the inflammatory activities in the DRG and the generation of pain. We also summarize the involvement of immune system, including immune cells and cytokines, in degenerated or herniated IVDs and affected DRG.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jsp2.1196

The involvement of immune system in intervertebral disc herniation and degeneration

Mesenchymal stromal cells isolated from bone marrow (MSC) represent an attractive source of adult stem cells for regenerative medicine. However, thorough research is required into their clinical application safety issues concerning a risk of potential neoplastic degeneration in a process of MSC propagation in cell culture for therapeutic applications. Expansion protocols could preselect MSC with elevated levels of growth-promoting transcription factors with oncogenic potential, such as c-MYC. We addressed the question whether c-MYC expression affects the growth and differentiation potential of human MSC upon extensive passaging in cell culture and assessed a risk of tumorigenic transformation caused by MSC overexpressing c-MYC in vivo. MSC were subjected to retroviral transduction to induce expression of c-MYC, or GFP, as a control. Cells were expanded, and effects of c-MYC overexpression on osteogenesis, adipogenesis, and chondrogenesis were monitored. Ectopic bone formation properties were tested in SCID mice. A potential risk of tumorigenesis imposed by MSC with c-MYC overexpression was evaluated. C-MYC levels accumulated during ex vivo passaging, and overexpression enabled the transformed MSC to significantly overgrow competing control cells in culture. C-MYC-MSC acquired enhanced biological functions of c-MYC: its increased DNA-binding activity, elevated expression of the c-MYC-binding partner MAX, and induction of antagonists P19ARF/P16INK4A. Overexpression of c-MYC stimulated MSC proliferation and reduced osteogenic, adipogenic, and chondrogenic differentiation. Surprisingly, c-MYC overexpression also caused an increased COL10A1/COL2A1 expression ratio upon chondrogenesis, suggesting a role in hypertrophic degeneration. However, the in vivo ectopic bone formation ability of c-MYC-transduced MSC remained comparable to control GFP-MSC. There was no indication of tumor growth in any tissue after transplantation of c-MYC-MSC in mice. C-MYC expression promoted high proliferation rates of MSC, attenuated but not abrogated their differentiation capacity, and did not immediately lead to tumor formation in the tested in vivo mouse model. However, upregulation of MYC antagonists P19ARF/P16INK4A promoting apoptosis and senescence, as well as an observed shift towards a hypertrophic collagen phenotype and cartilage degeneration, point to lack of safety for clinical application of MSC that were manipulated to overexpress c-MYC for their better expansion.

/pdf/impact-of-c-myc-expression-on-proliferation-differentiation-14qjm89v05.pdf

Impact of c-MYC expression on proliferation, differentiation, and risk of neoplastic transformation of human mesenchymal stromal cells

Degenerative disc disease (DDD) is a common cause of lower back pain with radicular symptoms and has a significant socioeconomic impact given the associated disability. Limited effective conservative therapeutic options result in many turning to surgical alternatives for management, which vary in the rate of success and also carry an increased risk of morbidity and mortality associated with the procedures. Several animal based studies and a few human pilot studies have demonstrated safety and suggest efficacy in the treatment of DDD with mesenchymal stem cells (MSCs). The use of bone marrow-derived MSCs for the treatment of DDD is promising and in the present study we report on the safety and efficacy findings from a registry based proof of concept study using a percutaneous intradiscal injection of cultured MSCs for the management of DDD with associated radicular symptoms. Thirty-three patients with lower back pain and disc degeneration with a posterior disc bulge diagnosed on magnetic resonance imaging (MRI) met the inclusion criteria and were treated with culture-expanded, autologous, bone marrow-derived MSCs. Prospective registry data was obtained at multiple time intervals up to 6 years post-treatment. Collected outcomes included numeric pain score (NPS), a modified single assessment numeric evaluation (SANE) rating, functional rating index (FRI), measurement of the intervertebral disc posterior dimension, and adverse events. Three patients reported pain related to procedure that resolved. There were no serious adverse events (i.e. death, infection, or tumor) associated with the procedure. NPS change scores relative to baseline were significant at 3, 36, 48, 60, and 72 months post-treatment. The average modified SANE ratings showed a mean improvement of 60% at 3 years post-treatment. FRI post-treatment change score averages exceeded the minimal clinically important difference at all time points except 12 months. Twenty of the patients treated underwent post-treatment MRI and 85% had a reduction in disc bulge size, with an average reduction size of 23% post-treatment. Patients treated with autologous cultured MSCs for lower back pain with radicular symptoms in the setting of DDD reported minor adverse events and significant improvements in pain, function, and overall subjective improvement through 6 years of follow-up. NCT03011398. A Clinical Registry of Orthobiologics Procedures. https://clinicaltrials.gov/ct2/show/NCT03011398?term=orthobiologics&rank=1

/pdf/treatment-of-lumbar-degenerative-disc-disease-associated-2w1gjl5fzv.pdf

Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy

Epidural steroid injections (ESI) are the most common pain management procedure performed in the US, however evidence of efficacy is limited. In addition, there is early evidence that the high dose of corticosteroids used can have systemic side effects. We describe the results of a case series evaluating the use of platelet lysate (PL) epidural injections for the treatment of lumbar radicular pain as an alternative to corticosteroids. Registry data was obtained for patients (N = 470) treated with PL epidural injections presenting with symptoms of lumbar radicular pain and MRI findings that were consistent with symptoms. Collected outcomes included numeric pain score (NPS), functional rating index (FRI), and a modified single assessment numeric evaluation (SANE) rating. Patients treated with PL epidurals reported significantly lower (p < .0001) NPS and FRI change scores at all time points compared to baseline. Post-treatment FRI change score means exceeded the minimal clinically important difference beyond 1 month. Average modified SANE ratings showed 49.7% improvement at 24 months post-treatment. Twenty-nine (6.3%) patients reported mild adverse events related to treatment. Patients treated with PL epidurals reported significant improvements in pain, exceeded the minimal clinically important difference (MCID) for FRI, and reported subjective improvement through 2-year follow-up. PL may be a promising substitute for corticosteroid.

/pdf/the-use-of-lumbar-epidural-injection-of-platelet-lysate-for-tu03tbu5c9.pdf

The use of lumbar epidural injection of platelet lysate for treatment of radicular pain

A New Atlanto-Occipital (C0-C1) Joint Injection Technique.

Bone marrow concentrate (BMC) has shown promise in the treatment of several orthopedic conditions This registry study investigated the use of autologous BMC and platelet products for percutaneous anterior cruciate ligament (ACL) treatment Twenty-nine patients presenting to a single outpatient interventional musculoskeletal and pain practice with symptomatic grade 1, 2, or 3 ACL tears with less than 1 cm retraction were enrolled Patients were treated with a percutaneous ACL injection of autologous BMC and platelet products using fluoroscopic guidance Pre- and post-treatment magnetic resonance imaging analysis was completed for 23 patients using ImageJ software for an objective quantitative analysis of pixel density as a proxy for ACL integrity Subjective clinical outcome measures collected pre-treatment and at 1, 3, 6, 12, 18, 24, and 36 months post-treatment include the Numerical Pain Scale (NPS), the Lower Extremity Functional Scale (LEFS), the International Knee Documentation Committee (IKDC) form, and a modified version of the Single Assessment Numeric Evaluation Seventy-seven percent of patients treated with BMC injections into the ACL showed significant improvement (p < 001) in objective measures of ACL integrity at an average of 88 months (median 47 months) The mean of last patient-reported improvement was 72% (SD = 35) at an average of 23 (SD = 10) months post-treatment Mean scores were found to be significantly different (p < 005) for the NPS at 6, 18, and 24 months, and LEFS and IKDC at all time points (ie 1, 3, 6, 12, 18, 24, and 36 months) relative to baseline In symptomatic patients with grade 1, 2, or even grade 3 tears with minimal retraction, ACL treatment with percutaneous injection of BMC and platelet products shows promise as a non-surgical alternative However, a larger randomized controlled trial is warranted to confirm these findings Trial registration NCT03011398 A Clinical Registry of Orthobiologics Procedures https://clinicaltrialsgov/ct2/show/NCT03011398?term=orthobiologics&rank=1
  Registered 29 December 2016 Enrollment 1 December 2011-retrospectively registered

/pdf/symptomatic-anterior-cruciate-ligament-tears-treated-with-57dmyzetzi.pdf

Symptomatic anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow concentrate and platelet products: a non-controlled registry study

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Papers

Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy

The use of lumbar epidural injection of platelet lysate for treatment of radicular pain

A New Atlanto-Occipital (C0-C1) Joint Injection Technique.

Symptomatic anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow concentrate and platelet products: a non-controlled registry study